Orally administrable opioid formulations having extended duration of effect

ABSTRACT

Sustained release oral solid dosage forms of opioid analgesics are provided as multiparticulate systems which are bioavailable and which provide effective blood levels of the opioid analgesic for at least about 24 hours. A unit dose of the opioid analgesic contains a plurality of substrates including the opioid analgesic in sustained release form. The substrates have a diameter from about 0.1 mm to about 3 mm.

This application is a continuation of U.S. application Ser. No.08/508,246 filed Jul. 27, 1995, now U.S. Pat. No. 5,968,551, which is acontinuation of U.S. application Ser. No. 08/133,503 filed Oct. 7, 1993,abandoned, which is a continuation-in-part of both U.S. patentapplication Ser. No. 08/081,618 filed Jun. 23, 1993, now U.S. Pat. No.5,472,712, and of U.S. patent application Ser. No. 08/086,248 filed Jul.1, 1993, abandoned, both of which are continuations-in-part of U.S.patent application Ser. No. 07/814,111, filed Dec. 24, 1991, now U.S.Pat. No. 5,273,760. U.S. application Ser. No. 08/133,503 is also acontinuation-in-part of U.S. patent application Ser. No. 08/097,558filed Jul. 27, 1993, now U.S. Pat. No. 5,580,578, which in turn is acontinuation-in-part of U.S. Ser. No. 07/826,084 filed Jan. 27, 1992,now U.S. Pat. No. 5,286,493.

BACKGROUND OF THE INVENTION

The present invention relates to bioavailable sustained-releasepharmaceutical formulations of analgesic drugs, in particular opioidanalgesics, which provide an extended duration of effect when orallyadministered.

It is known in the pharmaceutical art to prepare compositions whichprovide for controlled (slow) release of pharmacologically activesubstances contained in the compositions after oral administration tohumans and animals. Such slow release compositions are used to delayabsorption of a medicament until it has reached certain portions of thealimentary tract. Such sustained-release of a medicament in thealimentary tract further maintains a desired concentration of saidmedicament in the blood stream for a longer duration than would occur ifconventional rapid release dosage forms are administered.

Slow release formulations known in the art include specially coatedpellets, coated tablets and capsules wherein the slow release of theactive medicament is brought about through selective breakdown of thecoating of the preparation or through compounding with a special matrixto affect, the release of a drug. Some slow release formulations providefor related sequential release of a single dose of an active compound atpredetermined periods after administration.

It is the intent of all sustained-release preparations to provide alonger period of pharmacologic response after the administration of thedrug and is ordinarily experienced after the administration of the rapidrelease dosage forms. Such longer periods of response provide for manyinherent therapeutic benefits that are not achieved with correspondingshort acting, immediate a release preparations. This is especially truein the treatment of n cancer patients or other patients in need oftreatment for the alleviation of moderate to severe pain, where bloodlevels of an opioid analgesic medicament must be maintained at atherapeutically effective level to provide pain relief. Unlessconventional rapid acting drug therapy is carefully administered atfrequent intervals to maintain effective steady state blood levels ofthe drug, peaks and valleys in the blood level of the active drug occurbecause of the rapid absorption, systemic excretion of the compound andthrough metabolic inactivation, thereby producing special problems inmaintenance of analgesic efficacy.

The prior art teaching of the preparation and use of compositionsproviding the sustained-release of an active compound from a carrier isbasically concerned with the release of the active substance into thephysiologic fluid of the alimentary tract. However, it is generallyrecognized that the mere presence of an active substance in thegastrointestinal fluids does not, by itself, insure bioavailability.

In order to be absorbed, the active drug substance must be in solution.The time required for a given proportion of an active substance from aunit dosage form is determined as the proportion of the amount of activedrug substance released from a unit dosage form over a specified timebase by a test method conducted under standardized conditions. Thephysiologic fluids of the gastrointestinal tract are the media fordetermining dissolution time. The present state of the art recognizesmany satisfactory test procedures to measure dissolution time forpharmaceutical compositions, and these test procedures are described inofficial compendia world wide.

Although there are many diverse factors which influence the dissolutionof drug substance from its carrier, the dissolution time determined fora pharmacologically active substance from the specific composition isrelatively constant and reproducible. Among the different factorsaffecting the dissolution time are the surface area of the drugsubstance presented to the dissolution solvent medium, the pH of thesolution, the solubility of the substance in the specific solventmedium, and the driving forces of the saturation concentration ofdissolved materials in the solvent medium. Thus, the dissolutionconcentration of an active drug substance is dynamically modified in itssteady state as components are removed from the dissolution mediumthrough absorption across the tissue site. Under physiologic conditions,the saturation level of the dissolved materials is replenished from thedosage form reserve to maintain a relatively uniform and constantdissolution concentration in the solvent medium providing for a steadystate absorption.

The transport across a tissue absorption site of the gastrointestinaltract is influenced by the Donnan osmotic equilibrium forces on bothsides of the membrane since the direction of the driving force is thedifference between the concentrations of active substance on either sideof the membrane, i.e., the amount dissolved in the gastrointestinalfluids and the amount present in the blood. Since the blood levels areconstantly being modified by dilution, circulatory changes, tissuestorage, metabolic conversion and systemic excretion, the flow of activematerials is directed from the gastrointestinal tract into the bloodstream.

Notwithstanding the diverse factors influencing both dissolution andabsorption of a drug substance, a strong correlation has beenestablished between the in-vitro dissolution time determined for adosage form and (in-vivo) bioavailability. The dissolution time and thebioavailability determined for a composition are two of the mostsignificant fundamental characteristics for consideration whenevaluating sustained-release compositions.

It has previously been known in the art that sustained-releasecompositions of opioids or salts thereof could be prepared in a suitablematrix. For example, in U.S. Pat. Nos. 4,990,341 and 4,844,909 (Goldie,et al.), both assigned to the assignee of the present invention,describes hydromorphone compositions wherein the dissolution rate invitro of the dosage form, when measured by the USP Paddle or BasketMethod at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at37° C., is between 12.5 and 42.5% (by wt) hydromorphone released after 1hour, between 25 and 55%. (by wt) released after 2 hours, between 45 and75% (by wt) released after 4 hours and between 55 and 85% (by wt)released after 6 hours, the in vitro release rate being independent ofpH between pH 1.6 and 7.2 and chosen such that the peak plasma level ofhydromorphone obtained in vivo occurs between 2 and 4 hours afteradministration of the dosage form. At least 12 hours of pain relief isobtained with the hydromorphone formulations.

Once-a-day orally administrable dosage forms have previously beendeveloped in the art and are commercially available. However, currently,there are no orally administered opioid formulations commerciallyavailable which provide an extended duration of effect, e.g., greaterthan about 12 hours. Examples of commercially available once-a-daydosage forms include Dilacor® XR (diltiazem hydroxide, extended-releasecapsules, available from Rhone-Poulenc Rorer), Thorazine® Spanule®(chlorpromazine HCl, extended-release capsules, available fromSmithKline Beecham), Theo-24® (theophylline, extended-release capsules,available from Searle), TheoX® (theophylline, extended-release tablets,available from Carnrick), Theo-dur® (theophylline, extended-releasetablets, available from Key), Theo-Sav® (theophylline, extended-releasetablets, available from Sauage), Uniphyl® Unicontin® (theophylline,extended-release tablets, available from Purdue Frederick), T-Phyl®Unicontin® (theophylline, extended-release tablets, available fromPurdue Frederick), Tenuate Dospan® (diethylpropion HCl, extended-releasetablets, available from Marion Merrill Dow), Tepanil® Ten-Tab®(diethylpropion HCl, extended-release tablets, available from 3M Riker),Desoxyn® Gradumet® (phenmetrazine HCl, extended-release tablets,available from Abbott), Dexedrine® Spanule® (dextroamphetamine,extended-release capsules, available from SmithKline Beecham),Compazine® Spanule® (prochlorperazine maleate, extended-releasecapsules, available from SmithKline Beecham), Indocin® SR (indomethacin,extended-release capsules, available from Merck), Betachron®(propranolol HCl, extended-release capsules, available from Inwood),Inderal® LA (propranolol HCl, extended-release capsules, available fromWyeth-Ayerst), Inderide® LA (propranolol HCl and hydrochlorothiazide,extended-release capsules from Wyeth-Ayerst), Procardia XL® (nifedipine,extended-release tablets, available from Pfizer), Mestinon® Timespan®(pyridostigmine Br, extended-release tablets, available from ICN),Temaril® Spanule® (trimeprazine tartrate, extended-release capsules,available from Herbert), AL-R® 6 (chlorpheniramine maleate,extended-release capsules, available from Saron), Chlor-Trimeton®Allergy Repetabs® (chlorpheniramine maleate, extended-release tablets,available from Schering-Plough), Adipost® (phendimetrazine tartrate,extended-release capsules, available from Ascher), Bontril® Slow-Release(phendimetrazine tartrate, extended-release capsules, available fromCarnrick), Melfiat®-105 Unicelles® (phendimetrazine tartrate,extended-release capsules, available from Solway), Prelu-2®(phendimetrazine tartrate, extended-release capsules, available fromBoehringer Ingelheim), PT 105® (phendimetrazine tartrate,extended-release capsules, available from Legere), Wehless®-105Timecelles (phendimetrazine tartrate, extended-release capsules,available from Hauck), Preludin® Endurets® (phenmetrazine HCl,extended-release tablets, available from Boehringer Ingelheim),Caffedrine (caffeine, extended-release capsules, available from intoThompson), Diamox® Sequel® (acetazolamide, extended-release capsules,available from Storz), Verelan® (verapamil HCl, extended-releasecapsules cont. pellets, available from Wyeth-Ayerst), Calan® SR Caplets®(verapamil HCl, extended-release tablets, available from Searle),Isoptin® SR (verapamil HCl, extended-release tablets, available fromKnoll), Verapamil HCl Tablets (verapamil HCl, extended-release tablets,available from GoldLine), and Artane® Sequels® (trihexyphenidyl HCl,extended-release capsules, available from Lederle).

There is a need in the art to develop drug formulations which provide aduration of effect lasting longer than twelve hours such as a drug thatmay be administered to a patient only once a day. Many of the oralopioid analgesic formulations that are currently available in the marketmust be administered every four to six hours daily with a selected fewformulated for less frequent 12 hour dosing.

Morphine, which is considered to be the prototypic opioid analgesic, hasbeen formulated into 12 hour controlled-release formulations (i.e., MSContin® tablets, commercially available from Purdue Frederick Company).

An orally administrable opioid formulation which would provide anextended duration of effect would be highly desirable. Such an oralsustained-release formulation of an opioid analgesic would provideeffective steady-state blood levels (e.g., plasma levels) of the drugwhen orally administered such that a duration of effect greater than 12hours, and more preferably, of about 24 hours or more, which formulationis bioavailable as well.

OBJECTS AND SUMMARY OF THE INVENTION

It is accordingly an object of the present invention to provide anorally administered pharmaceutical dosage form of an opioid analgesicthat is suitable for once-a-day administration.

Another object of the present invention is to provide asustained-release products which provides effective steady-state bloodlevels in a human patient for greater than 12 hours, preferably at least24 hours, which products are bioavailable.

Still another object of the present invention is to provide a method oftreating a patient with an orally administrable dosage form of an opioidanalgesic which provides a desired analgesic effect for a period of timegreater than 12 hours, preferably for at least 24 hours and which dosageform is bioavailable.

In accordance with the above objects and others which will be apparentfrom the further reading of the specification and of the appendedclaims, the present invention is related to the surprising discoverythat in order to provide a 24 hour dosage form of an opioid analgesic,it is necessary to do so via a sustained multiparticulate system. Moreparticularly, the present invention is related to the surprisingdiscovery that while sustained-release tablets and sustained-releasemultiparticulate systems containing opioid analgesics may be preparedwhich provide an in-vitro dissolution indicative of a 24 hourformulation, only sustained-release multiparticulate systems of opioidanalgesics are bio-available. This is true even when thesustained-release tablets have an in-vitro dissolution profile which isvirtually equivalent to that provided by the multiparticulate system.

More particularly, the present invention relates to a sustained-releaseoral analgesic dosage form for once-a-day administration, comprising aunit dose of a plurality of inert pharmaceutically acceptablesubstrates. The unit dose of the substrates comprises an analgesicallyeffective amount of an opioid analgesic or a salt thereof. Each of saidsubstrates having a diameter from about 0.1 mm to about 3 mm. The unitdose is also bioavailable and provides effective blood levels of theopioid analgesic for at least about 24 hours. The unit dose of thesubstrates may be, for example, contained within a hard gelatin capsulefor oral administration.

In certain preferred embodiments of the present invention, each of thesubstrates has a diameter from about 0.5 mm to about 2 mm (narrowerrange).

The present invention is further related to a bio-availablesustained-release opioid analgesic dosage form for once-a-day oraladministration, comprising inert pharmaceutically acceptable beadshaving a diameter from about 0.1 mm to about 3 mm coated with ananalgesically effective amount of an opioid analgesic or a salt thereof.The beads further comprise a sustained-release overcoat comprising aneffective amount of a hydrophobic material selected from the groupconsisting of (i) an acrylic polymer such as copolymers of acrylic andmethacrylic acid; (ii) an alkylcellulose such as ethylcellulose; (iii)other commonly used retardant coatings such as shellac, zein, andhydrophobic waxy-type products, such as hydrogenated castor oil orhydrogenated vegetable oil, or (iv) mixtures of any of groups (i)-(iii)to provide a sustained-release of said opioid analgesic in aqueoussolutions for at least about 24 hours.

The present invention is further related to a method for obtaining abioavailable sustained-release opioid analgesic dosage form foronce-a-day oral administration, comprising preparing a plurality ofsubstrates comprising a unit dose of an oral analgesic in asustained-release form, each of which substrates having a diameter fromabout 0.1 mm to about 3 mm. The substrates are manufactured to providean in-vitro dissolution indicative of a once-a-day product.

The term “bioavailable” is defined for the purposes of the presentinvention as the total amount of a drug substance that is absorbed to beavailable to provide the desired therapeutic effect after administrationof a unit dosage form, as compared to the known reference drug product,as commonly determined and accepted by Governmental Regulatory Agencies,such as the United States FDA.

The term “bioavailability” is defined for purposes of the presentinvention as the extent to which the drug (e.g., opioid analgesic) isabsorbed from the unit dosage forms and becomes available at the site ofdrug action.

The terms “sustained release” and “extended duration” are defined forpurposes of the present invention as the release of the drug (e.g.,opioid analgesic) at such a rate that blood (e.g., plasma) levels aremaintained within the therapeutic range but below toxic levels over aperiod of time greater than 12 hours, more preferably for about 24hours, or longer.

The term “substrate” is defined for the purposes of the presentinvention as spheroids, beads, microspheres, seeds, pellets,ion-exchange resin beads, and other multi-particulate systems comprisingthe drug(s), which have a diameter from about 0.1 mm to about 3 mm,preferably between 0.5 mm and 2.0 mm.

The term “unit dose” is defined for purposes of the present invention asthe total amount of substrates needed to administer a desired dose ofdrug (e.g., opioid analgesic) to a patient.

The sustained-release substrates of the present invention permit releaseof the opioid (or salt) over a sustained period of time in an aqueousmedium. The term “aqueous medium” is defined for purposes of the presentinvention as any pharmaceutically acceptable dissolution medium, gastricfluid and/or intestinal fluid.

BRIEF DESCRIPTION OF THE DRAWING

The following drawing is illustrative of an embodiment of the inventionand is not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graphical representation of the formulation dissolutionobtained for Examples 1-4.

DETAILED DESCRIPTION

The multiparticulate systems of the present invention may incorporateone or more compounds known as opioid analgesics. Opioid analgesiccompounds which may be used in the present invention include alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, cyclazocine,desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, propheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tramadol,tilidine, salts thereof, mixtures of any of the foregoing, mixedmu-agonists/antagonists, mu-antagonist combinations, and the like.

In certain preferred embodiments, the opioid analgesic is selected frommorphine, codeine, hydromorphone, hydrocodone, oxycodone,dihydrocodeine, dihydromorphine, oxymorphone, or mixtures thereof.

In one preferred embodiment the sustained-release opioid oral dosageform of the present invention includes hydromorphone as thetherapeutically active ingredient in an amount from about 4 to about 64mg hydromorphone hydrochloride. Alternatively, the dosage form maycontain molar equivalent amounts of other hydromorphone salts or of thehydromorphone base. In other preferred embodiments where the opioidanalgesic is other than hydromorphone, the dosage form contains anappropriate amount to provide a substantially equivalent therapeuticeffect. For example, when the opioid analgesic comprises morphine, thesustained-release oral dosage forms of the present invention includeform about 5 mg to about 800 mg morphine, by weight. When the opioidanalgesic comprises oxycodone, the sustained-release oral dosage formsof the present invention include from about 5 mg to about 400 mgoxycodone.

The sustained-release dosage forms of the present invention generallyachieve and maintain therapeutic levels substantially withoutsignificant increases in the intensity and/or degree of concurrent sideeffects, such as nausea, vomiting or drowsiness, which are oftenassociated with high blood levels of opioid analgesics. There is alsoevidence to suggest that the use of the present dosage forms leads to areduced risk of drug addiction. Furthermore, the sustained-releasedosage forms of the present invention preferably release the opioidanalgesic at a rate that is independent of pH, e.g., between pH 1.6 and7.2. In other words, the dosage forms of the present invention avoid“dose dumping” upon oral administration.

In the present invention, the oral opioid analgesics have beenformulated to provide for an increased duration of analgesic actionallowing once-daily dosing. Surprisingly, these formulations, atcomparable daily dosages of conventional immediate-release drug, areassociated with a lower incidence in severity of adverse drug reactionsand can also be administered at a lower daily dose than conventionaloral medication while maintaining pain control.

The substrates of the present invention may further include one or moreadditional drugs which may or may not act synergistically with theopioid analgesics of the present invention. Examples of such additionaldrugs include non-steroidal anti-inflammatory agents, includingibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam or isoxicam, and the like. Other suitable additional drugswhich may be included in the dosage forms of the present inventioninclude acetaminophen, aspirin, and other non-opioid analgesics.

For example, if a second (non-opioid) drug is included in theformulation, such drug may be included in controlled release form or inimmediate release form. The additional drug may be incorporated into thecontrolled release matrix along with the opioid; incorporated into thecontrolled release coating; incorporated as a separated controlledrelease layer or immediate release layer; or may be incorporated as apowder, granulation, etc., in a gelatin capsule with the substrates ofthe present invention.

The sustained-release preparations of the present invention may be usedin conjunction with any multiparticulate system, such as beads,spheroids, microspheres, seeds, pellets, ion-exchange resin beads, andother multi-particulate systems in order to obtain a desiredsustained-release of the therapeutically active agent. Beads, granules,spheroids, or pellets, etc., prepared in accordance with the presentinvention can be presented in a capsule or in any other suitable unitdosage form.

When the substrates of the present invention are inert pharmaceuticalbeads, the inert pharmaceutical beads may be from about 8 mesh to about50 mesh. In certain preferred embodiments, the beads are, e.g., nupariel 18/20 beads.

In certain preferred embodiments of the present invention, thesustained-release opioid dosage forms comprise a plurality of substratescomprising the active ingredient, which substrates are coated with asustained-release coating. The coating formulations of the presentinvention should be capable of producing a strong, continuous film thatis smooth and elegant, capable of supporting pigments and other coatingadditives, non-toxic, inert, and tack-free.

In order to obtain a sustained-release of the opioid sufficient toprovide an analgesic effect for the extended durations set forth in thepresent invention, the substrate comprising the therapeutically activeagent may be coated with a sufficient amount of hydrophobic material toobtain a weight gain level from about 2 to about 30 percent, althoughthe overcoat may be greater depending upon the physical properties ofthe particular opioid analgesic compound utilized and the desiredrelease rate, among other things.

The solvent which is used for the hydrophobic material may be anypharmaceutically acceptable solvent, including water, methanol, ethanol,methylene chloride and mixtures thereof. It is preferable however, thatthe coatings be based upon aqueous dispersions of the hydrophobicmaterial.

In certain preferred embodiments of the present invention, thehydrophobic polymer comprising the sustained-release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cynaoethyl methacrylate, methyl methacrylate, copolymers, methacrylicacid copolymers, methyl methacrylate copolymers, methyl methacrylatecopolymers, methyl methacrylate copolymers, methacrylic acid copolymer,aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methylmethacrylate copolymers, poly(acrylic acid), poly(methacrylic acid,methacrylic acid alkylamide copolymer, poly(methyl methacrylate),poly(methacrylic acid) (anhydride), methyl methacrylate,polymethacrylate, methyl methacrylate copolymer, poly(methylmethacrylate), poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In one preferred embodiment, the acrylic coating is an acrylic resinlacquers used in the form of an aqueous dispersion, such as that whichis commercially available from Rohm Pharma under the TradenameEudragit®. In further preferred embodiments, the acrylic coatingcomprises a mixture of two acrylic resin lacquers commercially availablefrom Rohm Pharma under the Tradenames Eudragit® RL 30 D and Eudragit® RS30 D, respectively. Eudragit® RL 30 D and Eudragit® RS 30 D arecopolymers of acrylic and methacrylic esters with a low content ofquaternary ammonium groups, the molar ratio of ammonium groups to theremaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL 30 Dand 1:40 in Eudragit® RS 30 D. The mean molecular weight is about150,000. The code designations RL (high permeability) and RS (lowpermeability) refer to the permeability properties of these agents.Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids.However, coatings formed from the same are swellable and permeable inaqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain asustained-release formulation having a desirable dissolution profile.Desirable sustained-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

In other preferred embodiments, the hydrophobic polymer which may beused for coating the substrates of the present invention is ahydrophobic cellulosic material such as ethylcellulose. Those skilled inthe art will appreciate that other cellulosic polymers, including otheralkyl cellulosic polymers, may be substituted for part or all of theethylcellulose included in the hydrophobic polymer coatings of thepresent invention.

One commercially-available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic polymer, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic polymer will further improve the physical properties of thefilm. For example, because ethylcellulose has a relatively high glasstransition temperature and does not form flexible films under normalcoating conditions, it is necessary to plasticize the ethylcellulosebefore using the same as a coating material. Generally, the amount ofplasticizer included in a coating solution is based on the concentrationof the film-former, e.g., most often from about 1 to about 50 percent byweight of the film-former. Concentration of the plasticizer, however,can only be properly determined after careful experimentation with theparticular coating solution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tibutyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is especially preferred.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include citric acid esters such as triethyl citrate NFXVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propyleneglycol, polyethylene glycols, propylene glycol, diethyl phthalate,castor oil, and triacetin, although it is possible that otherwater-insoluble plasticizers (such as acetylated monoglycerides,phthalate esters, castor oil, etc.) may be used. Triethyl citrate isespecially preferred.

The sustained-release profile of the formulations of the invention canbe altered, for example, by varying the thickness of the hydrophobiccoating, changing the particular hydrophobic material used, or alteringthe relative amounts of, e.g., different acrylic resin lacquers,altering the manner in which the plasticizer is added (e.g., when thesustained-release coating is derived from an aqueous dispersion ofhydrophobic polymer), by varying the amount of plasticizer relative tohydrophobic polymer, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

Sustained-release spheroids or beads, coated with a therapeuticallyactive agent are prepared, e.g. by dissolving the opioid analgesic inwater and then spraying the solution onto a substrate, for example, nupariel 18/20 beads, using a Wurster insert. Optionally, additionalingredients are also added prior to coating the beads in order to assistthe hydromorphone binding to the substrates, and/or to color thesolution, etc. For example, a product which includes hydroxypropylmethylcellulose, etc. with or without colorant may be added to thesolution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the therapeutically active agent from the hydrophobicsustained-release coating. An example of a suitable barrier agent is onewhich comprises hydroxypropyl methylcellulose. However, any film-formerknown in the art may be used. It is preferred that the barrier agentdoes not affect the dissolution rate of the final product.

The hydromorphone, HPMC protected (optional) beads may then beovercoated with hydrophobic polymer, preferably with an effective amountof plasticizer.

The coating solutions of the present invention may contain, in additionto the film-former, plasticizer, and solvent system (i.e., water), acolorant to provide elegance and product distinction. Color may be addedto the solution of the therapeutically active agent instead, or inaddition to the aqueous dispersion of hydrophobic polymer.

The plasticized aqueous dispersion of hydrophobic polymer may be appliedonto the substrate comprising the therapeutically active agent byspraying using any suitable spray equipment known in the art. In apreferred method, a Wurster fluidized-bed system is used in which an airjet, injected from underneath, fluidizes the core material and effectsdrying while the acrylic polymer coating is sprayed on. A sufficientamount of the aqueous dispersion of hydrophobic polymer to obtain apredetermined sustained-release of said therapeutically active agentwhen said coated substrate is exposed to aqueous solutions, e.g. gastricfluid, is preferably applied, taking into account the physicallycharacteristics of the therapeutically active agent, the manner ofincorporation of the plasticizer, etc. After coating with thehydrophobic polymer, a further overcoat of a film-former, such asOpadry®, is optionally applied to the beads. This overcoat is provided,if at all, in order to substantially reduce agglomeration of the beads.

Next, the coated beads are cured in order to obtain a stabilized releaserate of the therapeutically active agent.

When the coating comprises an aqueous dispersion of ethylcellulose, thecoated substrate is preferably subjected to curing at a temperaturegreater than the glass transition temperature of the coating solution(i.e., ethylcellulose) and at a relative humidity from about 60% toabout 100%, until the curing endpoint is reached, e.g., about 60° C. anda relative humidity from about 60% to about 100% for a time period fromabout 48 to about 72 hours.

In preferred embodiments of the present invention directed to theacrylic coating, a stabilized product is obtained by subjecting thecoated substrate to oven curing at a temperature above the Tg of theplasticized acrylic polymer for the required time period, the optimumvalues for temperature and time for the particular formulation beingdetermined experimentally. In certain embodiments of the presentinvention, the stabilized product is obtained via an oven curingconducted at a temperature of about 45° C. for a time period from about24 to about 48 hours or longer.

The release of the therapeutically active agent from thesustained-release formulation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition of one ormore release-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic polymer to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic polymers such ashydroxypropylmethylcellulose.

The sustained-release coatings of the-present invention can also includeerosion-promoting agents such as starch and gums.

The sustained-release coatings of the present invention can also includematerials useful for making microporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained-release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of whichare hereby incorporated by reference). The passageway can have any shapesuch as round, triangular, square, elliptical, irregular, etc.

In other embodiments of the present invention, the present invention mayutilize a multiparticulate sustained-release matrix. Suitable materialsfor inclusion in a sustained-release matrix are

(a) Hydrophilic polymers, such as gums, cellulose ethers, acrylic resinsand protein derived materials. Of these polymers, the cellulose ethers,especially hydroxyalkylcelluloses and carboxyalkylcelluloses, arepreferred. The oral dosage form may contain between 1% and 80% (byweight) of at least one hydrophilic or hydrophobic polymer.

(b) Digestible, long chain (C₈C₅₀, especially C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes.Hydrocarbons having a melting point of between 25° and 90° C. arepreferred. Of these long chain hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

(c) Polyalkylene glycols. The oral dosage form may contain up to 60% (byweight) of at least one polyalkylene glycol.

For example, a suitable matrix may be one which comprises at least onewater soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy(C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form will be determined, inter alia, by the precise rate ofopioid release required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. In certainpreferred embodiments, the at least one aliphatic alcohol is cetylalcohol or cetostearyl alcohol. The amount of the at least one aliphaticalcohol in the present oral dosage form will be determined, as above, bythe precise rate of opioid release required. It will also depend onwhether at least one polyalkylene glycol is present in or absent fromthe oral dosage form. In the absence of at least one polyalkyleneglycol, the oral dosage form preferably contains between 20% and 50% (bywt) of the at least one aliphatic alcohol. When at least onepolyalkylene glycol is present in the oral dosage form, then thecombined weight of the at least one aliphatic alcohol and the at leastone polyalkylene glycol preferably constitutes between 20% and 50% (bywt) of the total dosage.

In one embodiment, the ratio of, e.g., at least one hydroxyalkylcellulose or acrylic resin to at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of the at leastone hydroxyalkyl cellulose to at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

At least one polyalkylene glycol may be, for example, polypropyleneglycol or, preferably, polyethylene glycol. The number average molecularweight of the at least one polyalkylene glycol is preferred between 1000and 15000 especially between 1500 and 12000.

Another suitable sustained-release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In addition to the above ingredients, a sustained-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

In order to facilitate the preparation of a solid, sustained-releaseoral dosage form according to this invention there is provided, in afurther aspect of the present invention, a process for the preparationof a solid, sustained-release oral dosage form according to the presentinvention comprising incorporating opioids or a salt thereof in asustained-release matrix. Incorporation in the matrix may be effected,for example, by

(a) forming granules comprising at least one water soluble hydroxyalkylcellulose and opioid or an opioid salt,

(b) mixing the hydroxyalkyl cellulose containing granules with at leastone C₁₂-C₃₆ aliphatic alcohol, and

(c) optionally, compressing and shaping the granules. Preferably, thegranules are formed by wet granulating the hydroxyalkyl cellulose/opioidwith water. In a particularly preferred embodiment of this process, theamount of water added during the wet granulation step is preferablybetween 1.5 and 5 times, especially between 1.75 and 3.5 times, the dryweight of the opioid.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active ingredient can be spheronized to form spheroids.Microcrystalline cellulose is preferred. A suitable microcrystallinecellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Corporation). In such embodiments, in addition to the activeingredient and spheronizing agent, the spheroids may also contain abinder. Suitable binders, such as low viscosity, water soluble polymers,will be well known to those skilled in the pharmaceutical art. However,water soluble hydroxy lower alkyl cellulose, such as hydroxy propylcellulose, are preferred. Additionally (or alternatively) the spheroidsmay contain a water insoluble polymer, especially an acrylic polymer, anacrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer,or ethyl cellulose. In such embodiments, the sustained-release coatingwill generally include a water insoluble material such as (a) a wax,either alone or in admixture with a fatty alcohol; or (b) shellac orzein.

The substrates of the present invention may also be prepared via a meltpellitization technique. In such circumstance, the opioid in finelydivided form is combined with a binder (also in particulate form) andother optional inert ingredients, and thereafter the mixture ispelletized, e.g., by mechanically working the mixture in a high shearmixer to form the pellets (granules, spheres). Thereafter, the pellets(granules, spheres) may be sieved in order to obtain pellets of therequisite size. The binder material is preferably in particulate formand has a melting point above about 40° C. Suitable binder substancesinclude, for example, hydrogenated castor oil, hydrogenated vegetableoil, other hydrogenated fats, fatty alcohols, fatty acid esters, fattyacid glycerides, and the like.

In certain embodiments of the invention, the sustained release dosageform of the present invention provides a peak plasma level of the opioidin-vivo from about 2 to about 10 hours after administration, preferablyfrom about 2 to about 4 hours after administration.

In certain embodiments of the present invention, an effective amount ofopioid in immediate release form is included in the unit dose comprisingthe substrates of the present invention. The immediate release form ofthe opioid is included in an amount which is effective to shorten thetime to maximum concentration of the opioid in the blood,(e.g., plasma),such that the T_(max) is shortened to a time of, e.g., from about 2 toabout 4 hours. This causes the blood concentration curve to have anearly peak rather than the substantially flattened curves currentlyrecommended by those skilled in the art. It has been discovered that byincluding such an effective amount of immediate release opioid in theunit dose, the experience of relatively higher levels of pain inpatients is significantly reduced. In such embodiments, an effectiveamount of the opioid in immediate release form may be coated onto thesubstrates of the present invention. For example, where the extendedrelease opioid from the formulation is due to a controlled releasecoating, the immediate release layer would be overcoated on top of thecontrolled release coating. On the other hand, the immediate releaselayer may be coated onto the surface of substrates wherein the opioid isincorporated in a controlled release matrix. Where a plurality of thesustained release substrates comprising an effective unit dose of theopioid are incorporated into a hard gelatin capsule, the immediaterelease portion of the opioid dose may be incorporated into the gelatincapsule via inclusion of the sufficient amount of immediate releaseopioid as a powder or granulate within the capsule. Alternatively, thegelatin capsule itself may be coated with an immediate release layer ofthe opioid. One skilled in the art would recognize still otheralternative manners of incorporating the immediate release opioidportion into the unit dose. Such alternatives are deemed to beencompassed by the appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1 Sustained-Release Beads With Ethylcellulose Coating

In Example 1, morphine sulfate sustained-release beads with a 5% w/wsustained-release of ethylcellulose were prepared, including 3% of HPMCas a pore-former in the coating.

Morphinesulfate beads are first manufactured using a rotor processingtechnique. The formula of the morphine sulfate bead to which thesustained-release coating is applied is set forth in Table 1 below:

TABLE 1 Amt/Unit Ingredient (mg) Percent (%) Morphine Sulfate Powder 30mg 14.3% Lactose Hydrous Impalpable 42.5 mg 20.2% PVP 2.5 mg 1.2% SugarBeads 18/20 125 mg 59.4% Purified Water qs — Opadry ® Red YS-1-1841 10.5mg 4.9% Total 210.5 mg 100.0%

The morphine sulphate beads were then overcoated with asustained-release coating. The formula for the sustained-release coatingis set forth in Table 2 below:

TABLE 2 Amt/Unit Ingredient (mg) Percent (%) Morphine Sulfate Base Beads210.5 mg 89.7% Aquacoat ECD 30 (solids) 10.2 mg 4.3% Methocel E5 premium0.3 mg 0.1% Triethyl Citrate 2.1 mg 0.9% Purified Water qs — Opadry ®Red YS-1-1841 11.7 mg 5.0% Purified Water qs — Total 234.8 mg 100.0%

The sustained-release coating was manufactured as follows:

The pore former Methocel E5 Premium (HPMC), is dispersed and dissolvedin purified water to yield a 2% w/w solution. An Aquacoat dispersion isplasticized with triethyl citrate for approximately 30 minutes. After 30minutes the HPMC dispersion is mixed into the plasticized Aquacoatdispersion, and blended for an additional 15-30 minutes. A load of themorphine sulfate beads is charged into a Uniglatt Wurster Insertequipped with a 1.2 mm fluid nozzle. The beads are then filmcoated withthe Aquacoat/HPMC dispersion (in a ratio of 93:7) to a weight gain of5%.

After completion of the coating process, the coated beads are taken fromthe Wurster Insert to a tray and then cured in a chamber at atemperature of 60° C. and humidity of 80% RH for 72 hours. Uponcompletion of the curing process, the beads are dried to a LOD of 4% orless. The beads are then given a final overcoating of Opadry® RedYS-1-1841 (15% w/w solution) with the use of the Wurster Insert. Thecoated morphine sulfate beads are then filled into hard gelatincapsules.

Dissolution testing were conducted on the finished products via USPApparatus II-(Paddle Method). The capsules were placed into 700 ml ofsimulated gastric fluid (without enzymes) for the first hour at 100 rpmand 37° C., and then placed into 900 ml of simulated gastric fluid(without enzymes) after the first hour.

The results are set forth in Table 3 below:

TABLE 3 Percent Morphine Time Sulfate Dissolved  1 hour 18.4%  2 hours28.4%  4 hours 46.7%  8 hours 73.1% 12 hours 86.0% 18 hours 95.0% 24hours 99.0%

The dissolution testing as set forth in Table 3 indicates that 100% ofthe morphine sulfate dissolved after 12 hours.

EXAMPLE 2 Sustained-Release Beads With Acrylic Polymer Coating

In example 2, morphine sulfate sustained-release beads with a 5% w/wsustained-release Eudragit RS were prepared, including a 10% immediaterelease morphine sulfate overcoat.

Morphine sulfate beads are first manufactured using a rotor processingtechnique. The formula of the morphine sulfate bead to which thesustained-release coating is applied is set forth in Table 4 below:

TABLE 4 Amt/Unit Ingredient (mg) Percent (%) Morphine Sulfate Powder 30mg 14.3% Lactose Hydrous Impalpable 42.5 mg 20.2% PVP 2.5 mg 1.2% SugarBeads 18/20 1.25 mg 59.4% Purified Water qs mg — Opadry Red YS-1-184110.5 mg 4.9% Total 210.5 mg 100.0%

A sustained-release coating was then applied to the morphine sulfatebeads. The formula for the functional coating is set forth in Table 5below:

TABLE 5 Amt/Unit Ingredient (mg) Percent (%) Morphine Base Beads 189.45mg 86.7% Retardant Coating Eudragit RS 30D 9.5 mg 4.3% Triethyl Citrate1.9 mg 0.9% Talc 3.8 mg 1.7% Purified Water qs — Overcoat MorphineSulfate Powder 3.0 mg 1.4% Opadry Red YS-1-1841 10.8 mg 5.0% PurifiedWater qs — Total 218.45 mg 100.0%

The sustained-release coating is manufactured as follows:

The Eudragit RS 30D is plasticized with triethyl citrate and talc forapproximately 30 minutes. A load of the morphine sulfate beads ischarged into a Wurster insert of a Glatt equipped with a 1.2 mm spraynozzle and the beads are coated to a weight gain of 5%. The finalprotective Opadry dispersion overcoat is then applied in the WursterInsert. Upon completion the beads are cured for two days in a dry ovenof 45° C. The cured beads were then filled into gelatin capsules at a 30mg strength.

Dissolution testing were conducted on the gelatin capsules via U.S.P.Apparatus II (Paddle Method). The capsules were placed into 700 ml ofsimulated gastric fluid (without enzymes) for the first hour at 100 rpmand 37° C., and then placed into 900 ml of simulated gastric fluid(without enzymes) after the first hour. The results of the percent ofmorphine sulfate dissolved in relation to time, are set forth in Table 6below:

TABLE 6 Percent Morphine Time Sulfate Dissolved  1 hour 11.9%  2 hours15.4%  4 hours 28.1%  8 hours 58.3% 12 hours 79.2% 18 hours 92.0% 24hours 96.6%

The dissolution testing as set forth in Table 6 indicates that 96.6% ofthe morphine sulfate dissolved after 24 hours.:

EXAMPLE 3 High Load Sustained-Release Beads With Acrylic Polymer Coating

In certain circumstances, patients require higher doses of morphinesulfate. However, if the low load beads of Examples 1 and 2 were filledto a weight equivalent to 60 mg or more, the capsules would berelatively large, and difficult to swallow. Therefore, in Example 3,beads with a higher loading of morphine sulfate were produced with theuse of the powder layering technique in the Glatt Rotor Processor. Theformulation of the high load beads, as well as a comparison of the highload beads with the low load beads of Examples 1 and 2,are set forth inTable 7 below:

TABLE 7 High Load Low Load Bead Bead Percent (Examples 1 & PercentIngredient mg/unit (%) 2) mg/unit (%) Morphine Sulfate  30.0 mg 63.3% 30.0 mg 14.3% Powder Lactose  6.0 mg 12.7%  42.5 mg 20.2% Povidone C-30 1.25 mg 2.6%  2.5 mg 1.2% Sugar Beads  7.75 mg 16.4% 125.0 mg 59.4%Opadry  2.37 mg 5.0%  10.5 mg 4.9% Purified Water qs — qs — Total 47.37mg 100.0% 210.5 mg 100.0%

Since high load beads of Example 3 are different from the low load beadsof Examples 1 and 2, the sustained-release coating a different acrylicpolymer (i.e., Eudragit® RL, which is more soluble than Eudragit® RS) isutilized, as well as extra HPMC protective coat between the Eudragitlayer and the morphine immediate release layer to further enhancestability. The formula of the sustained-release coating of Example 3 isset forth in Table 8 below:

TABLE 8 Amt/Unit Ingredient (mg) Percent (%) Morphine (high load) basebeads 42.63 mg 78.8% Retardant Coating Eudragit RS 30D 2.1 mg 3.9%Eudragit RL 30D 0.05 mg 0.1% Triethyl Citrate 0.45 mg 0.8% Talc 0.85 mg1.6% Overcoatings Opadry Blue YS-1-10542A 2.45 mg 4.5% Purified Water qs— Morphine Sulfate Powder 3.0 mg 5.5% Opadry Blue YS-1-10542A 2.55 mg4.8% Purified Water qs — Total 54.08 mg 100.0%

The sustained-release and the immediate release coatings were applied inthe manner described in Example 2. The cured beads were then filled intogelating capsules at a strength of 30 mg.

The capsules were then subjected to dissolution testing applying themethod described in Example 1. The results of dissolution testing is setforth in Table 9 below:

TABLE 9 Percent Morphine Time Sulfate Dissolved  1 hour 11.7%  2 hours12.1%  4 hours 22.0%  8 hours 45.3% 12 hours 63.7% 18 hours 81.8% 24hours 92.5%

The dissolution testing as set forth in Table 9 indicates that 92.5% ofthe morphine sulfate dissolved after 24 hours.

EXAMPLE 4 Sustained-Release Tablets

Controlled release morphine sulfate tablets were developed with anin-vitro dissolution profile that would be suitable for, once-a-dayadministration. The formula of the morphine sulfate tablets is set forthin Table 10 below.

TABLE 10 Amt/Unit Ingredient (mg) Percent (%) Morphine Sulfate  60.0 mg40.0% Lactose  36.1 mg 24.1% Povidone  6.0 mg 4.0% Eudragit RS 36D(solids)  12.0 mg 8.0% Triacetin  1.4 mg 0.9% Cetostearyl alcohol  30.0mg 20.0% Talc  3.0 mg 2.0% Magnesium stearate  1.5 mg 1.0% Total 150.0mg 100.0%

These tablets are manufactured in the following manner:

The morphine sulfate, lactose and povidone were added and mixed in fluidbed granulator. The triacetin, a plasticizer was mixed into the EudragitRS 30D dispersion for-about 30 minutes, and then was sprayed onto thepowders using a 1.2 mm nozzle in the fluid bed. Once the spraying iscompleted, the granulate is screened. The cetostearyl alcohol is thenmelted and mixed into the granulation in a standard mixing bowl. Thegranulate is then cooled, screened and lubricated with-talc andmagnesium stearate. Tablets were then compressed at a weight of 150 mg.

Dissolution testing of these morphine sulfate tablets was then conductedusing the method described in Example 1. The results of the dissolutiontesting of these tablets is set forth in Table 11 below:

TABLE 11 Percent Morphine Time Sulfate Dissolved  1 hour 20.9%  2 hours29.3%  4 hours 40.8%  8 hours 59.9% 12 hours 69.7% 18 hours 82.9% 24hours 90.5%

The results of dissolution of the morphine sulfate tablets as set forthin Table 11 shows that 90.5% of the morphine sulfate dissolved in 24hours.

Examples 1, 2, 3 and 4 were plotted on a dissolution graph (see FIG. 1)and it can be observed that the dissolution of the morphine sulfatetablets of Example 4 are approximately the same as the three beadexamples. The release rate of the tablets of Example 4 lies with thedissolution of the bead products (Examples 1-3). For reference purposes,the dissolution of MS Contin® 30 mg and 60 mg tablets were also plottedon FIG. 1. MS Contin® tablets are well known morphine sustained-releasetablets that are commercially available from the Purdue FrederickCompany for twice-a-day administration.

EXAMPLE 5 In-Vivo Bioavailibility Studies

The bead products of Examples 1, 2 and 3 were then studied in separatehuman bioavailability studies at a dose of 30 mg. Each study also used a30 mg strength MS Contin® as a reference in a cross-over design. The 60mg tablet of Example 4 was compared to MS Contin® 60 mg as a referencein a cross-over study. The results of all four bioavailability studiesare set forth in Tables 12-15 below. In Table 16, the in-vivo results ofExample 4 are set forth with the results adjusted to a 30 mg strength.In each of Tables 12-16, C_(max) is expressed in ng/ml; T_(max) isexpressed in hours; W₅₀ represents the peak width at half height inhours; and AUC represents the area under the curve (0 to infinity),expressed in ng-hr/ml.

TABLE 12 Beads - Example 1 C_(max) T_(max) W50 AUC % Bioavail. MSContin ® 13 2.3 5 103 (100) 30 mg Tablets Experimental 5.9 5.6 11.5 101 98 Bead Formulation

TABLE 12 Beads - Example 1 C_(max) T_(max) W50 AUC % Bioavail. MSContin ® 13 2.3 5 103 (100) 30 mg Tablets Experimental 5.9 5.6 11.5 101 98 Bead Formulation

TABLE 14 Beads - Example 3 C_(max) T_(max) W50 AUC % Bioavail. MSContin ® 11.8 2.8 5 114 (100) 30 mg Tablets Experimental 3.8 10.1 47 125110 Bead Formulation

TABLE 14 Beads - Example 3 C_(max) T_(max) W50 AUC % Bioavail. MSContin ® 11.8 2.8 5 114 (100) 30 mg Tablets Experimental 3.8 10.1 47 125110 Bead Formulation

TABLE 14 Beads - Example 3 C_(max) T_(max) W50 AUC % Bioavail. MSContin ® 11.8 2.8 5 114 (100) 30 mg Tablets Experimental 3.8 10.1 47 125110 Bead Formulation

From the bioavailability studies, it can be observed that all three ofthe bead products of Examples 1, 2 and 3 exhibit pharmacokineticproperties which would aglow them to be suitable for once-a-dayadministration. In other words, the bead products of Examples 1-3 wereall bioavailable (as determined by comparing the AUC of the bead productto the AUC of the reference standard, MS Contin®). However, the tabletproducts-of Example 4 were surprisingly not bioavailable despite thereduction of the peak plasma concentration (c_(max)) and the lengtheningof the time to reach peak plasma concentration (T_(max)) and W-50 andeven though the dissolution studies show that the morphine sulfate wasreleased from the tablet products in-vitro over the same time period asthe bead products.

Therefore, it is surprising result that a bioavailable once-a-dayproduct was only produced when the sustained release opioid wasformulation as a multiparticulate system (in this instance beads) asopposed to the sustained release tablet formulation, which from allother indications would have been expected to have substantiallyidentical bioavailability.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

What is claimed is:
 1. A bioavailable sustained-release oral analgesicdosage form for once-a-day administration, comprising: a unit dosecomprising an analgesically effective amount of a plurality ofpharmaceutically acceptable matrices comprising an opioid analgesic or asalt thereof, and a hydrophobic material selected from the groupconsisting of an alkylcellulose, an acrylic resin and mixtures thereof,said matrices further comprising at least one C₁₂ to C₃₆ aliphaticalcohol, each of said matrices having a diameter from about 0.1 mm toabout 3 mm, said dosage form being bioavailable and providing atherapeutic effect for about 24 hours or more after oral administrationto a human patient.
 2. A bioavailable sustained-release oral analgesicdosage form for once-a-day administration, comprising: a unit dosecomprising a plurality of pharmaceutically acceptable matricescomprising an analgesically effective amount of hydromorphone or a saltthereof, ethylcellulose and stearyl alcohol, each of said matriceshaving a diameter from about 0.1 mm to about 3 mm, said dosage formbeing bioavailable and providing a therapeutic effect for about 24 hoursor more after oral administration to a human patient.
 3. The dosage formof claim 1, wherein said matrices further comprise at least onepolyalkylene glycol.
 4. The dosage form of claim 1, wherein said C₁₂ toC₃₆ aliphatic alcohol is stearyl alcohol.
 5. The dosage form of claim 1,wherein said opioid analgesic is selected form the group consisting ofmorphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone,dihydrocodeine, dihydromorphine, tramadol, and mixtures thereof.
 6. Thedosage form of claim 1, wherein said opioid analgesic is selected fromthe group consisting of alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, codeine, cyclazocine, desomorphine, dextromoramide,dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixturesthereof.
 7. The dosage form of claim 5, wherein said opioid analgesicconsists of from about 2 mg to about 64 mg hydromorphone.
 8. The dosageform of claim 5, wherein said opioid analgesic consists of from about 5mg to about 800 mg morphine.
 9. The dosage form of claim 1, wherein saidopioid analgesic consists of from about 5 mg to about 400 mg oxycodone.10. The dosage form of claim 1 which provides a peak plasma level ofsaid opioid in-vivo from about 2 to about 10 hours after administration.11. The dosage form of claim 1 which provides a peak plasma level ofsaid opioid in-vivo from about 2 to about 4 hours after administration.12. The dosage form of claim 1, wherein said matrices further comprise ahydroxyalklcellulose selected from the group consisting ofhydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose and mixtures of any of the foregoing.
 13. Thedosage form of claim 12, wherein said hydroxyalkylcellulose ishydroxyethylcellulose.
 14. The dosage form of claim 1, wherein said unitdose of said matrices are contained within a hard gelatin capsule. 15.The dosage form of claim 1, wherein said matrices have a diameter fromabout 0.5 mm to about 2 mm.
 16. A bioavailable sustained-release oralanalgesic dosage form for once-a-day administration, comprising: a unitdose comprising a plurality of pharmaceutically acceptable matricescomprising an analgesically effective amount of tramadol or a saltthereof, ethylcellulose and stearyl alcohol, each of said matriceshaving a diameter from about 0.1 mm to about 3 mm, said dosage formbeing bioavailable and providing a therapeutic effect for about 24 hoursor more after oral administration to a human patient.
 17. The dosageform of claim 1, further comprising release-modifying agents, saidrelease-modifying agents comprising one or more hydrophilic polymers.18. A dosage form of claim 1, further comprising a non-opioid drug. 19.The dosage form of claim 18, wherein the said non-opioid drug is anon-steroidal anti-inflammatory agent.
 20. The dosage form of claim 19,wherein said non-steroidal anti-inflammatory agent is selected from thegroup consisting of ibuprofen, diclofenac, naproxen, benoxaprofen,flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen,carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen,aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin,sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin,fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid,flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal,piroxicam, sudoxicam or isoxicam, and mixtures of any of the foregoing.21. The dosage form of claim 1, wherein said opioid analgesic consistsof tramadol or a salt thereof.
 22. The dosage form of claim 1, whereinsaid alkylcellulose is ethylcellulose.
 23. The dosage form of claim 2which provides a peak plasma level of said opioid in-vivo from about 2to about 10 hours after administration to a patient or a population ofpatients.
 24. The dosage form of claim 2 which provides a peak plasmalevel of said opioid in-vivo from about 2 to about 4 hours afteradministration to a patient or a population of patients.
 25. The dosageform of claim 16 which provides a peak plasma level of said opioidin-vivo from about 2 to about 10 hours after administration to a patientor a population of patients.
 26. The dosage form of claim 16 whichprovides a peak plasma level of said opioid in-vivo from about 2 toabout 4 hours after administration to a patient or a population ofpatients.